PT  - JOURNAL ARTICLE
AU  - Hiroko Morimoto
AU  - Mito Kanastu-Shinohara
AU  - Narumi Ogonuki
AU  - Satoshi Kamimura
AU  - Atsuo Ogura
AU  - Chihiro Yabe-Nishimura
AU  - Yoshifumi Mori
AU  - Takeshi Morimoto
AU  - Satoshi Watanabe
AU  - Kinya Otsu
AU  - Takuya Yamamoto
AU  - Takashi Shinohara
TI  - ROS amplification drives mouse spermatogonial stem cell self-renewal
AID  - 10.26508/lsa.201900374
DP  - 2019 Apr 01
TA  - Life Science Alliance
PG  - e201900374
VI  - 2
IP  - 2
4099  - https://www.life-science-alliance.org/content/2/2/e201900374.short
4100  - https://www.life-science-alliance.org/content/2/2/e201900374.full
SO  - Life Sci. Alliance2019 Apr 01; 2
AB  - Reactive oxygen species (ROS) play critical roles in self-renewal division for various stem cell types. However, it remains unclear how ROS signals are integrated with self-renewal machinery. Here, we report that the MAPK14/MAPK7/BCL6B pathway creates a positive feedback loop to drive spermatogonial stem cell (SSC) self-renewal via ROS amplification. The activation of MAPK14 induced MAPK7 phosphorylation in cultured SSCs, and targeted deletion of Mapk14 or Mapk7 resulted in significant SSC deficiency after spermatogonial transplantation. The activation of this signaling pathway not only induced Nox1 but also increased ROS levels. Chemical screening of MAPK7 targets revealed many ROS-dependent spermatogonial transcription factors, of which BCL6B was found to initiate ROS production by increasing Nox1 expression via ETV5-induced nuclear translocation. Because hydrogen peroxide or Nox1 transfection also induced BCL6B nuclear translocation, our results suggest that BCL6B initiates and amplifies ROS signals to activate ROS-dependent spermatogonial transcription factors by forming a positive feedback loop.